Abstract Sepsis causes >250,000 deaths each year in the USA. Lipopolysaccharide (LPS), shed by gram-negative bacteria, alone is sufficient to induce cytokine storm and sepsis. Meanwhile, many other infections and diseases can also cause sepsis. Sepsis is complex, dynamic, and heterogeneous in both etiology and progression, which has led to failures of almost all unimodal immune modulation therapies. The systemic hyperinflammation in sepsis is generally induced by circulating LPS, pathogenic and damage molecules and signaling molecules (e.g. cytokines). Therefore, physical clearance of these septic triggers and mediators from blood is a valid approach for sepsis treatment. A polymyxin B-coated cartridge, Toraymyxin, has been used to remove LPS specifically by hemoperfusion (HP). Recently, a Cytosorb cartridge packed with macroporous resin is used to remove cytokines through nonspecific hydrophobic adsorption. Unfortunately, both products failed in the most recent double-blind controlled clinical trials for sepsis treatment, which is likely due to the moderate efficiency and limited adsorption profiles of both cartridges. In addition, various proinflammatory damage molecules should also be removed for the treatment to be effective. Therefore, we hypothesize that the efficient and simultaneous removal of both septic triggers and mediators from the circulation will control hyperinflammation in sepsis, and thus reducing both morbidity and mortality associated with severe sepsis and septic shock. The PI has developed a versatile telodendrimer (TD) nanoplatform for efficient binding to LPS, cytokines, and DNA fragments via the combination of multivalent and synergistic charge and hydrophobic interactions. Such TD nanotraps can be conjugated onto size-exclusive hydrogel resins to target these small-sized proinflammatory molecules. These nanotrap resins are able to selectively scavenge LPS and proinflammatory cytokines efficiently in the blood from septic mice with much higher efficiencies than existing commercial resins. The charge and hydrophobic moieties in the nanotrap can be easily engineered to target a specific group of inflammatory molecules to optimize sepsis treatment. Aim 1, we will focus on synthesis and optimization of TD nanotraps with different charges and hydrophobic moieties on hydrogel resins and characterize the selectivity and efficiency in adsorbing LPS, DAMP/PAMPs and cytokines; Aim 2, We will conduct comprehensive in vitro studies to characterize the refined nanotrap adsorption and understand the molecular basis in attenuating hyper-immune reactions; Aim 3, we will study the efficacy of nanotrap HP approach in Cecal Ligation and Puncture (CLP) septic rat model and characterize the in vivo immune reactions and pathological improvement in preventing multiple organ failure. These studies will pave the way to translate this innovative HP nanotrap technique into the clinic to improve the survival of patients with severe sepsis and septic shock. It can also be used to treat patients with high risk of a cytokine storm, e.g. cardiac surgery, burn, trauma and CAR-T cancer immunotherapy.